Prostate cancer is the most common malignancy in men and the second leading cause of cancer mortality in the United States (Wingo P. et al., Cancer statistics, Cancer J Clin 45: 8-30 (1995)). The disease can progress with markedly different clinical outcomes. An understanding of the difference between aggressive and nonaggressive tumors at the molecular level has been hindered by the diverse cell types present in the prostate gland and an inability to derive pure cell populations for genetic study.
The Gleason score is a reliable prognosticator for disease progression at both ends of the histologic spectrum (≦4 or ≧8). Poor disease outcome in the more prevalent Gleason range (5 to 7) is best predicted by a positive surgical margin, capsular penetration, and seminal vesicle invasion (Epstein J. et al., Prediction of progression following radical prostatectomy: a multivariate analysis of 721 men with long-term follow-up, Am J Surg Pathol 20: 286-292 (1996)). However, these parameters can only be assessed after major surgery. Certain cases of prostate cancer respond to surgical and/or pharmaceutical intervention. Others metastasize rapidly, by mechanisms that remain poorly understood, to tissues such as bone.
Currently available diagnostic methods directed to the detection of prostate cancer focus largely on prostate specific antigen (PSA). This protein is known to be a glycosylated serine protease, and is produced in relatively large quantities in the epithelial cells of the prostate and is secreted in seminal fluid. Smaller amounts are detected in the serum of healthy individuals; higher serum concentrations are thought to be correlated with pathological conditions such as prostate cancer. Other diagnostic methods address nucleic acids differentially expressed in prostate cancer.
U.S. Pat. No. 5,674,682 issued Oct. 7, 1997, to Croce et al. relates to methods for detecting prostate cancer micrometastasis, in which a sample containing nucleic acids is amplified and probed by hybridization to particular oligonucleotide probes. These probes are disclosed as being specific for prostate cancer.
U.S. Pat. No. 5,658,730 issued Aug. 19, 1997, to McGill et al., entitled “Methods of Human Prostate Cancer Diagnosis”, discloses diagnostic techniques for the detection of human prostate cancer. A set of degenerate probes is used to detect gene amplification in prostate cancer cells at regions of chromosome 8q24.1-24.2. A comparison of the probe sequence with the specific primers used reveals no significant segments sharing identity between either of the specific primers and the disclosed probe. Copy number changes of chromosome 8q serve as a marker for the development of aggressive prostate cancers.
U.S. Pat. No. 5,622,829 issued Apr. 22, 1997, to King et al., entitled “Genetic Markers for Breast, Ovarian and Prostatic Cancer”, discloses the nucleotide sequences for several alleles of BRCA1. The specification suggests ascertaining men at risk for prostatic cancer in view of female siblings or family members diagnosed for breast cancer. Several alleles of BRCA1 are disclosed. A method of screening a patient for prostatic cancer susceptibility based on hybridizing with nucleic acids comprising the sequences provided is also claimed.
U.S. Pat. No. 5,614,372 issued Mar. 25, 1997, to Lilja et al. relates to a bioaffinity assay of PSA using monoclonal antibodies in which a measure of PSA is related to the total of the concentration of PSA plus human glandular kallikrein-1 present in a sample of body fluid. The PSA level determined may be either the concentration of free PSA (i.e., uncomplexed PSA) or the concentration of PSA complexed with alpha-1 anti-chymotrypsin. The assay results permit discrimination between benign prostatic hyperplasia and prostate cancer.
U.S. Pat. No. 5,552,277 issued Sep. 3, 1996, to Nelson et al., entitled “Genetic Diagnosis of Prostate Cancer”, teaches that prostatic glutathione-S-transferase promoter becomes hypermethylated in most prostatic cancers. Nelson et al. discloses a method of detecting the hypermethylated promoter in view of its altered susceptibility to a methylation-sensitive restriction nuclease.
U.S. Pat. No. 5,543,296 issued Aug. 6, 1996, to Sobol et al. entitled “Detection of Carcinoma Metastases by Nucleic Acid Amplification”, discloses a method for detecting metastasis of a prostate carcinoma which entails treating a sample of non-prostate tissue in such a way as to amplify mRNA for PSA. A method for detecting carcinoma metastases in body tissues and fluids is disclosed only in general, broad terms; prostatic acid phosphate [sic, phosphatase] and PSA are mentioned only at col. 12, 1, 23-26. Several primers are disclosed.
U.S. Pat. No. 5,506,106 issued Apr. 9, 1996, to Croce et al., entitled “Methods of Detecting Micrometastasis of Prostate Cancer”, discloses a procedure for diagnosing prostate cancer metastasis by seeking mRNA from PSA among the population of nucleated cells in a blood sample, using RT-PCR with PSA-specific primers.
U.S. Pat. No. 5,501,983 issued Mar. 26, 1996 to Lilja et al. entitled “Assay of Free and Complexed Prostate-Specific Antigen”, discloses methods of immunoassay for measuring PSA both free and as a proteinase inhibitor complex.
In spite of these advances, there remains a need to develop prognostic tumor markers that can be measured in limited needle biopsies early in the progression of prostate cancer, especially in the case of aggressive prostate cancer. There further remains a need to address more selective and specific assays for various types of prostate cancer. Assays are needed that permit distinguishing prostate cancer from non-neoplastic prostate disease. Furthermore there is a need to develop diagnostic methods that facilitate identifying prostate cancers of differing aggressiveness and metastatic potential. There is likewise a need for the diagnostic probes on which such methods are founded. This invention addresses these needs.